Prophylactic compositon for scours



Patented Aug. 19, 1952 UNITED STATES PATENT OFFICE PROPHYLACTIOCOMPOSITION FOR SCOURS I Karl Paul Link, Middleton, Wis., assignor to Wis- 'co'nsin Alumni Research Foundation, Madison Wis., a corporation of Wisconsin No Drawing. Application August 2, 1949, Serial No. 108,233

or weeks of life primarily ascribed to scours is estimated at :20 per cent. Also, according to the U. S. D. A. Yearbook, Keeping Live Stock Healthy, U. S. Gov. Printing Office (1942), -40 per cent of lambs may die in severe outbreaks of dysentery sometimes called white scours, whilst 50 per cent of new-born pigs may die of enteritis (or three day pig disease) "and scours. 2

The chief symptoms preceding death are diarrhea (hence the name scours), inflammation of theumbilical stump, and a general exudative arthritis. M

The primary cause of scours is strains of bacteria of the colon group (Bacillus 'coli or ooli aerogenes) encountered by the new-born for the first time and against whom a resistance must be developed for survival. Colon group bacteria of this type are non-pathogenic under normal conditions, B. 0012 being the first organism to establish itself in the large intestine after birth.

dom from cold and dampness, and where infection is present theisolation-ofinfected animals. In highly virulent epizootics of scours, however, all or nearly all; of the young may'become irrfeeted andsurvival varies depending on, the 'de-'- gree of resistance and vigor that has-been developed "shortly after 'birth. This is particularly;

the situation with the calf, lamb andpig which unlike the ape and man, get little or no'immu'ne bodies +by-=intrauterine or patent-a1 *tranm 2 I sion. It is also applicable to rabbits and the like which fall between man and the ruminant of the calf type.

The new-born mammal is for all practical purposes born in a state of physiologic shock. Hemorrhagic petechiae are present in the intestinal tract which is essentially a delicate raw membrane. Within 7-10 days, a very noticeabl morphological change sets in and the hemorrhagicpetechiae largely disappear from the tract. Adjustment must be made from a wet (physiologically balanced) to a dry, unbalanced environment. Adjustment'must also-be made to two new conditions (a) fluid balance and (b) nourishment by mouth as opposed to nourishment 'via the placenta. Imposed on these is the urgent necessity of developing re-,

sistance to the new bacterialflora encountered. The changemay be stated as: r

Septic environment (Outside the uterus) Immunity must be developed Aseptic environment,

(In the uterus) Immunity via the mother The problem presented by scours has been recognized for 'many years and many specific preventative measures and recipes for treatment, particularly for calf scours have been proposed.

The preventive measures for calf scours include assurance that the calf receives an ample supply of colostrum, isolation of mother and call to clean quarters, use of a muzzle to prevent the calf from eating contaminated litter and overeating, injection of antibacterial serum-bovine, the feeding of milk diluted with lime water, feeding acidophilus milk, administration of vitamin A and certain members of the B complex and use of sulfa drugs. Udall, D. H., The Practice of Veterinary Medicine, Utica, N. '.Y., 5th ed, 1947.

The-feeding of milk diluted with water has also been proposed, Sheehy, J., The Scientific Prooeedings ofthe Royal Dublin Society, '21, (N. S.)' No. 9, 73 (1934).

The treatment of "choice for the prophylaxis of scour -is an "amplesupply of'bovin'e colostrum ('thefirst milk) since it has been demonstrated that it 'contain's'in-addition to the essential food elements, immune proteins or 'antibodieswhich' at; are were). a

473; 483; 519 (1930) has also beenemployed. as

.4 tained from mammalian blood and preferably from non-citrated pooled blood of dairy cattle or blood from sheep, pigs, etc. The blood may be secured by the bleeding of the animals including animals which have been specially treated to provide hyper-immune blood, although a readily available and satisfactory source of blood is that available in the processing of animals at an abattoir. The immune proteins carried in plasma, serum, Howes NazSOi globulin fraction or the like, may be produced from the blood by processing the blood in accordance with standard serum-bovine) Smith, T., Jour. Exp. Med. "51, I

a prophylactic (and cure). This proposal though I scientifically sound has not been widely adopted in all probability because the serum needs to be injected intravenously and this requires the services of skilled personnel such as a veterinarian.

In place of commercially prepared serum, the use of the dams blood (defibrinated and citrated) has also been proposed, the administration being intravenous or subcutaneous. This practice has not met wide adoption, even though recognized to be effective, since it requires the use of skilled technicians, see Udall, supra.

Next to colostrum, the sulfa drugs are probably the most widely used for the prevention of calf scours. The use of the sulfa drugs, however,

is not without risk due to'their toxic effects;

Wise and Anderson, supra. The other preventive measures listed above have been used to alimited extent but each has its shortcomings. Udall,

supra. I, V n

Thev art has long desired an effective, nontoxic, commercially practical prophylacticfor scour that can be given orally. In particular, the art has desired a relatively inexpensive com position readily adaptable for use on farms,

ranches and the like that does not require for administration the services of medically skilled personnel. a r

The principal object of the present invention is to provide an effective, non-toxic composition for preventing or inhibiting scours incalves, lambs, goats, pigs, rabbits and .the like.

Another object of the present invention is to:

provide an efiective composition for preventing scours that can be given orally.

A further object of the present invention is to cially available ingredients that actively cooperate to produce an effective composition for preventing or inhibiting scours. Thelcompbsition which is administered per os contains as essential ingredients immune bodies from blood,

together with a small but effective amount of vitamin K or a compound characterized by. vita.- min K' anti-hemmorrhagic activity. 'Iioiscombination may be used with a Ringer-Tyrode salt.

mixture or with suitable food for the new-born animal such as colostrum, 'milk solids and the like, and for oral feeding can be incorporated into water or in water containing the Ringer-Tyrode physiological salt mixture r i I une proteins: or?

Immune bodies.--The' V v n A v antibodies used in the present invention are 910%;

practices in the art. The desired plasma, serum for globulin fraction may be spray dried or be subjected to freeze-drying. Satisfactory procedures are described in the Medical Research Council Report No. 258, The Preservation of Proteins by Drying, by R. I. N. Greaves, H. M. S. Stationary Ofilce (1946).

Vitamin K.The vitamin K or vitamin K compound used in the present invention may be natural vitamin K, such as K1 or K2, or various natural or synthetic compounds which pro.- mote the formation or activation of prothrombin. Some of the effective compounds are 25 methyl-1,4-naphthoquinone (Menadione); 2- methyl-1,4-naphthohydroquinone-3-sodium, sulfonate (Hykinone) 4 amino 2 methyl 1 naphtho-lhydrochloride (Synkamin) Z-methyl- 3-hydroxy-L4-naphthoquinone (Phthiocol) 2- methyl 1,4 naphthohydroquinone diphosphoric acid ester tetrasodium salt (Synkay- Vite); 2-methyl-1,4 naphthohydroquinone; 2- methyl-1,4-naphthohydroquinone diacetate and 2 methyl 1,4 dihydroxy 3 naphtholalde hyde. When a water insoluble vitamin K composition such .as natural K1 or K2 is employed, the addition of bile salts to facilitate absorption is recommended. I v

The following examples will serve to illustrate the invention.

1 v o 319% rare? it? arm-reset gram; glucose, 1.0 gram.

The plasma is prepared from pooled dairy cow blood in accordance withv standard practices in the art, and then spray dried or freeze dried. The vitamin K. (commercially available under the name- Menadion e) is a crystalline solid. The partially (or enzyme) digested milk solids are prepared by treating cows milk with pancreatingforabout one hour at 40 C., the digestedpmixture; pasteurized at 775 for thirty minutes'and 'then' SD dI In each example the ingredients are intimately mixed. in the dry state, and then storedfinlajsuitable stoppered container in V which ,form lthe mi ure are I t e ,w e kept; refrigerated;

When ready for administration sufiicient water is added for every 50 grams of plasma to provide one liter of composition. It is ordinarily preferred to administer the composition from a drench bottle or it can be fed from a pail. In practice it is preferred to offer an equal volume of water immediately after administrationor the composition containing 50 grams of plasma With or without the digested milk solids and with or without the Ringer-Tyrode salt mixture, can be made up to 2 liters directly and administered in that dilution.

For a calf two feedings of a composition containing 50 grams of plasma in one or two liter volumes each per day for two to four days is generally satisfactory. For smaller animals such as the rabbit, oral administration (via a wide tipped dropper) of about 2-4 cc. of the composition of Example C (from a suspension containing 200 grams per liter) daily increasing up to about -12 cc. by the seventh day has proven satisfactory. For example, in a colony of rabbits particularly susceptible to scours (mucoid enteritis) where the survival was approximately 52%, the administration of the composition of Example C of the present invention increased the survival to about 85%.

The proportions of ingredients employed above are merely illustrative; and they may be varied to meet particular needs. When using plasma and milk solids it is ordinarily preferred to use at least about one part of partially digested mill; solids to one part of plasma, and in most instances it is preferred to use compositions containing a major proportion (60-90 per cent) of milk solids and a minor proportion (10-40 per cent) of plasma. The three to one ratio (75 per cent milk solids to per cent plasma) employed in Example C has been found to give excellent results in practice. The amount of vitamin K compound used may also be varied within wide limits depending, for example, upon the activity or anti-hemorrhagic characteristics of the vitamin K compound selected, etc. Preferably the vitamin K compound is used in excess and in all cases is present in suflicient amounts to substantially reduce the extent'and duration of hypoprothrombinemia (a condition found in newborn) and the persistence of the hemorrhagic petechiae in the intestinal tract. A composition providing a daily dosage of around 40 to 80 mg. of Menadione is indicated for relatively large animals.

Investigations have demonstrated that the immune proteins (antibodies) used in the present invention when absorbed unaltered from the alimentary canal and into the blood in active condition passively immunize new-born animals against B. coli and related organisms causing scours. See Smith, T. and Little, R. B., Jour. Exp. Med. 30, 181, (1922); Smith, E. and Holm, A., Jour. Biol. Chem. 175, 349 (1948). Investigations have also demonstrated that such immune bodies are readily absorbed unaltered and in active condition from the digestive tract of newborn up to about '7 to 10 days after birth when administered with vitamin K.

The vitamin K used in the composition of the present invention reduces the extent and duration of hypoprothrombinemia and the persistence of hemorrhagic petechiae, i. e. minute hemorrhages in the digestive tract. The action on the digestive tract is of utmost importance as it blocks portals for entry of scour producing organisms into the blood stream. Also, at the same time the administration of vitamin K changes the normally hemorrhagic condition of the digestive tract of the new-born to a nonhemorrhagic condition more suitable for rapid absorption of the immune bodies into the blood. The operation of the basic (immune body-vitamin K) ingredients of the present invention thus involves cooperative action of the type long desired for preventing scours.

It will be understood that the present invention is not limited to the above illustrative examples and that the use of equivalent materials fall within the scope of the invention. Examples are the use of serum (defibrinated blood) and immune fractions such as Howes N 3.2804 globulin fraction and the like, in place of the plasma described above. It will also be understood that the composition of the present invention may be used to combat scours in various animals including the rabbit, pig, goat and lamb as well as the calf.

I claim: 4

1. A non-toxic composition for oral administration having utility in the prophylaxis of scours, comprising as essential ingredients immune proteins derived from mammalian blood and a vitamin K compound.

2. A non-toxic composition for oral administration having utility in the prophylaxis of scours, comprising bovine plasma containing immune proteins derived from the blood of dairy cattle and a vitamin K compound.

3. A non-toxic composition for oral administration having utility in the prophylaxis of scours, comprising bovine serum containing immune proteins derived from the blood of dairy cattle and a vitamin K compound.

4. A non-toxic composition for oral administration having utility in the prophylaxis of. scours, comprising as essential ingredients immune proteins derived from the blood of cattle and a vitamin K compound.

5. A non-toxic composition for oral administration having utility in the prophylaxis of scours, comprising bovine plasma containing immune proteins derived from the blood of cattle and menadione in a ratio of 1-2 grams per 2500 grams of plasma.

KARL PAUL LINK.

REFERENCES CITED The following references are of record in the file of this patent:

Gutman: Modern Drug Encyclopedia, edition (1946), page 58.

Wise: Journal of Dairy Science, vol. 27, pages 965 to 979. 

1. A NON-TOXIC COMPOSITION FOR ORAL ADMINISTRATION HAVING UTILITY IN THE PROPHYLAXIS OF SCOURS, COMPRISING AS ESSENTIAL INGREDIENTS IMMUNE PROTEINS DERIVED FROM MAMMALIAN BLOOD AND A VITAMIN K COMPOUND. 